ClinVar Miner

Submissions for variant NM_000209.4(PDX1):c.226G>A (p.Asp76Asn)

gnomAD frequency: 0.00320  dbSNP: rs137852783
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics, part of Exact Sciences RCV000246150 SCV000302992 benign not specified criteria provided, single submitter clinical testing
GeneDx RCV000948405 SCV000518497 likely benign not provided 2021-05-20 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 28323911, 15170499, 15277425, 19515026, 10720084, 24097065, 10545531, 10545530, 26669242)
Personalized Diabetes Medicine Program, University of Maryland School of Medicine RCV000445407 SCV000537091 benign Monogenic diabetes 2018-10-12 criteria provided, single submitter research ACMG criteria: BS2 (cases=controls in PMID 17592437, 21569088), BS1 (0.4% MAF in gnomAD)= benign; REVEL 0.245 +BP4/4 predictors + PP3/6 predictors: conflicting evidence, not using) OMIM suggests that it is a susceptability factor for T2DM
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000009409 SCV000746931 benign Type 2 diabetes mellitus 2023-12-10 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000626294 SCV000746953 benign Maturity onset diabetes mellitus in young 2023-12-10 criteria provided, single submitter clinical testing
Invitae RCV000948405 SCV001094610 benign not provided 2024-01-20 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000948405 SCV001144244 benign not provided 2019-07-16 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000030077 SCV001423109 benign Maturity-onset diabetes of the young type 4 2020-01-22 criteria provided, single submitter curation The p.Asp76Asn variant in PDX1 (sometimes called IPF1) has been reported in at least 32 individuals with Maturity-Onset Diabetes of the Young (PMID: 15277425, 10545531, 10545530, 17592437), and has been identified in 0.4909% (336/68440) of European (non-Finnish) chromosomes, including 2 homozygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs137852783). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. However, this variant does not segregate with disease in many families, including sibling pairs (PMID: 10545531, 15277425). This variant has also been reported as a benign variant, likely benign variant, VUS, likely pathogenic variant, and risk factor for diabetes in ClinVar (Variation ID: 8859). In vitro functional studies provide some evidence that the p.Asp76Asn variant may slightly impact protein function, but this evidence is not conclusive (PMID: 10545531). These types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, this variant meets criteria to be classified as benign for Maturity-Onset Diabetes of the Young in an autosomal dominant manner based on a higher than expected frequency in control cohorts and nonsegregation with MODY. ACMG/AMP Criteria applied: BS2, BS4, BP4 (Richards 2015).
Genetic Services Laboratory, University of Chicago RCV000246150 SCV002068921 likely benign not specified 2020-01-08 criteria provided, single submitter clinical testing
Ambry Genetics RCV000626294 SCV002733265 likely benign Maturity onset diabetes mellitus in young 2022-06-22 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000948405 SCV003799703 likely benign not provided 2023-09-14 criteria provided, single submitter clinical testing
OMIM RCV001799501 SCV000029627 uncertain significance Diabetes mellitus type 2, susceptibility to 1999-11-01 no assertion criteria provided literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000030077 SCV000052732 not provided Maturity-onset diabetes of the young type 4 2011-08-18 no assertion provided clinical testing

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